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<p>Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with current therapies failing to achieve significant clinical advancements. GDPPH1, a natural compound derived from <i>Garcinia mangostana L</i>., is known for its antioxidant properties; however, its anticancer effects and underlying mechanisms remain insufficiently understood. In this study, we demonstrate that GDPPH1 significantly inhibits GBM cell proliferation in a concentration-dependent manner by downregulating CDK4 and Cyclin D1 expression, inducing cell cycle arrest at G1/S checkpoint, and promoting apoptosis. Mechanistically, GDPPH1 reduces the m<sup>6</sup>A methylation of <i>CDK4</i> and <i>CCND1</i> through METTL14-YTHDF2-mediated transcript decay, resulting in decreased <i>CDK4</i>/<i>CCND1</i> expression and subsequent decreased RB phosphorylation levels. Further studies revealed that m<sup>6</sup>A-METTL14-YTHDF2 axis is responsible for GDPPH1-induced downregulation of CDK4 and Cyclin D1. Additionally, the in vivo anti-GBM efficacy of GDPPH1 was confirmed using both xenograft and orthotopic intracranial mouse models. Collectively, these findings provide robust evidence supporting GDPPH1 as a promising therapeutic candidate for GBM and offer novel insights into the role of m<sup>6</sup>A RNA methylation in cell cycle regulation.</p>

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GDPPH1 induces cell cycle arrest by downregulation of CDK4/Cyclin D1 via the m6A-METTL14-YTHDF2 axis, attenuating glioblastoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Sijia Li,
  • Ruijie Yuan,
  • Jinxuan Su,
  • Ruxi Chen,
  • Xinyi Qu,
  • Lele Zhao,
  • Xiaofeng Zhou,
  • Qiuming Zou,
  • Zhijing Zhang,
  • Siyu Yang,
  • Jianqin Lai,
  • Xiaosong Zhuang,
  • Zisheng Li,
  • Kai Cui,
  • Shengwei Hu,
  • Yongqi Liu,
  • Lili Liu,
  • Zepeng Luo,
  • Zhongping Luo,
  • Wen Li,
  • Yu Yan,
  • Yubo Zhang,
  • Zhiming Zheng,
  • Qi Qi

摘要

Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with current therapies failing to achieve significant clinical advancements. GDPPH1, a natural compound derived from Garcinia mangostana L., is known for its antioxidant properties; however, its anticancer effects and underlying mechanisms remain insufficiently understood. In this study, we demonstrate that GDPPH1 significantly inhibits GBM cell proliferation in a concentration-dependent manner by downregulating CDK4 and Cyclin D1 expression, inducing cell cycle arrest at G1/S checkpoint, and promoting apoptosis. Mechanistically, GDPPH1 reduces the m6A methylation of CDK4 and CCND1 through METTL14-YTHDF2-mediated transcript decay, resulting in decreased CDK4/CCND1 expression and subsequent decreased RB phosphorylation levels. Further studies revealed that m6A-METTL14-YTHDF2 axis is responsible for GDPPH1-induced downregulation of CDK4 and Cyclin D1. Additionally, the in vivo anti-GBM efficacy of GDPPH1 was confirmed using both xenograft and orthotopic intracranial mouse models. Collectively, these findings provide robust evidence supporting GDPPH1 as a promising therapeutic candidate for GBM and offer novel insights into the role of m6A RNA methylation in cell cycle regulation.